PROJECTSUMMARY/ABSTRACT Theprocessofagingcausesfunctionaldeclineofthehematopoieticsystem,includingreducedcapacityfor regeneration,increasedriskofinfections,andincreasedriskofcertainformsofbloodcancer.Thisisa significanthealthconcernduetotheincreasingageofourpopulationandincidenceoftheseage-related conditions.Nointerventiontherapiescurrentlyexisttoextendhematopoietichealthspanwithaging,largelydue toalackofunderstandingofthecellularandmolecularalterationsthatcausefunctionalhematopoieticdecline. Ournovelapproachistoidentifycellularandmolecularsignaturesoffunctionalhematopoieticdeclineatits ageofonset,withtherationalethatthesesignatureswillpointtoearlycausesofdeclineandhenceidentify primetargetsforextendinghematopoietichealthspan.Ourpreliminarydatademonstratethatfunctional hematopoieticdeclineoccursbymiddleage,thatalterationsinthebonemarrowmicroenvironmentatmiddle agearenecessaryandsufficienttocausefunctionalhematopoieticdecline,andidentifyalterationsinthe Insulin-likeGrowthFactor1(IGF1)signalingpathwayatmiddleageasastrongcandidatedriveroffunctional hematopoieticdecline.Thisprojectwillusecellularandmolecularbiologicalapproachesinagingmiceto characterizethehematopoieticcell-extrinsicandcell-intrinsicalterationsinIGFsignalingatmiddleagethat causefunctionalhematopoieticdecline.Resultsofthisprojectwillidentifytargeted,molecular-andcelltype- specifictherapeuticstrategiestopreserveregenerativecapacityandimmunecellfunctionduringaging.